While millions of HIV-infected patients in sub-Saharan Africa are now receiving life-saving antiretroviral therapy, early mortality is much higher than expected, and the extent of CD4+ T cell recovery is highly variable. Understanding the predictors of CD4+ T cell recovery will be important to optimize the effectiveness of antiretroviral treatment programs in sub-Saharan Africa. We hypothesize that persistent generalized T cell activation is an important determinant of blunted CD4+ T cell recovery in sub-Saharan Africans. While T cell activation declines significantly during suppressive antiretroviral therapy, it remains abnormally elevated and has been associated with blunted CD4+ T cell recovery in resource-rich settings. While the determinants of T cell activation remain unknown, stimulation of innate immune responses by residual HIV replication and by other co- infections are likely mechanisms. HIV and co-infections may stimulate innate immune responses by activating natural killer (NK) cells through killer immunoglobulin-like receptor (KIR) - human leukocyte antigen (HLA) interactions and by binding toll-like receptors (TLR). Several KIR/HLA allotypes and TLR polymorphisms have been associated with activation or inhibition of innate immune responses to HIV and prevalent co-infections and with clinical progression during untreated HIV-1 infection. Whether these host genetic factors are associated with T cell activation and CD4+ T cell recovery during suppressive antiretroviral therapy remains unknown. We propose to assess whether KIR/HLA allotypes and TLR polymorphisms are associated with persistent T cell activation (% CD38+ HLA-DR+ CD8+ T cells) and the rate of CD4+ T cell recovery in 400 HIV-infected Ugandans maintaining viral suppression on their first antiretroviral treatment regimen and followed every 3 months for a median of 24 months. We will perform these studies using samples from the well- characterized UARTO cohort in Mbarara, Uganda (a representative cohort of HIV- infected Ugandans intiating antiretroviral therapy) and in collaboration with the Carrington lab at NCI-Frederick;the UCSF Genomics Core Facility;and the Cao Laboratory in Kampala, Uganda. This work will help identify inflammatory pathways influencing treatment-mediated CD4+ T cell recovery, identifying targets for interventions to optimize the effectiveness of antiretroviral therapy in sub-Saharan Africa. PUBLIC HEALTH RELEVANCE: While millions of HIV-infected patients in sub-Saharan Africa are finally receiving life- saving HIV medications, death rates remain high, and many fail to regain normal immune function. Excessive stimulation of the innate immune system by residual HIV replication and other prevalent infections like tuberculosis and malaria may prevent full recovery of the immune system in these patients. This research project will help identify inflammatory pathways that prevent immune system recovery in these patients, eventually leading to targeted interventions to improve immune system recovery.